Transdermal Tobacco Alkaloid Patch

ABSTRACT

The invention relates to a tobacco alkaloid patch ( 10; 41; 42; 43; 51; 52; 53; 54 ) for transdermal administration of a tobacco alkaloid, said patch comprising an impermeable backing ( 11 ) and a membrane ( 14 ) which defines a cavity ( 12 ) there between, said membrane being permeable to and in contact with said tobacco alkaloid, said impermeable backing and said membrane being at least partly joined by a sealing and wherein the width ( 17 ) of said sealing is at least about 1 mm. 
     According to the invention an improved low-area tobacco alkaloid patch has been obtained.

FIELD OF THE INVENTION

The invention relates to a transdermal reservoir patch according toclaim 1.

BACKGROUND OF THE INVENTION

The invention relates to a transdermal reservoir patch and in particularto a transdermal nicotine patch. The nicotine patches are generallyintended to be applied for a regular and relatively constant maintenanceof nicotine or a corresponding tobacco alkaloid in the blood of a userin order to avoid craving.

Transdermal devices for the delivery of a wide variety ofphysiologically active substances have been known for some time andtransdermal devices in the form of reservoir patches are disclosed ine.g. U.S. Pat. No. 5,254,346 and in the form of matrix patches in e.g.U.S. Pat. No. 6,165,497. Such devices generally comprise an impermeablebacking, a drug or physiologically active substance reservoir, a ratecontrolling membrane and an adhesive layer which by some means aresealed together to produce a transdermal delivery device.

Matrix designs, where drug provided as a semisolid with no membrane anddrug-in-adhesive (DIA) are the dominant products on the marketpresently. The development of such technologies is relatively complexand costly. These designs require long-term compatibility among thedrug, adhesive and excipients. Thus, the demands made on the adhesivemay be somewhat stricter than those on reservoir systems. On the otherhand, reservoir patches have certain disadvantages when applied as atobacco alkaloid releasing patch compared to matrix or drug-in adhesivepatches.

A general problem of matrix patches is that the area must be quitesignificant in order to deliver a desired amount of nicotine. Thus, somematrix patches has areas around 30 cm² in order to deliver 10 to 20 mgduring a period of 16 hours.

A problem of prior art transdermal patches may be that the stiffness ofthe boundary region of the patches might cause troubles. The stiffnesscan have several causes but no matter which, it has the effect that theymight be uncomfortable to wear for the user. First a matrix as thecentral part of the transdermal patch will stiffen the patch and therebypotentially make it less comfortable. Second the width of the sealing ofthe different layers of the patch will give stiffness to the outerborder of the patch and thereby cause a total increased stiffness. Asmentioned stiffness from a rigid boundary of the patch is annoying forthe user as the stiffness of the patch might cause a rim of irritationaround the patch causing e.g. a minor slicing in the skin of the user.Moreover, it might as well cause a worse attachment to the skin and aworse attachment to the skin gives a risk of clothing getting stuck tothe patch and nicotine escaping into the surroundings instead of beingdelivered to the user.

Especially for matrix patches, the combination of the large dimensionsof the patch and the stiffness might cause a higher risk of a corner ofthe patch releasing from the skin of the user and thereby causingnicotine to escape the skin of the user by evaporating into the air.

In order to overcome the problem of insufficient attachment of the patchthe producers of matrix patches have added a larger amount of adhesivewith a following extra irritation to the user.

A problem of e.g. applying a reservoir patches for nicotine delivery isthat reservoir patches may have an even lower comfort level than matrixdesign, as the design would tend to be stiffer and less comfortable thancorresponding matrix designs.

This problem is believed to be one of the reasons why nicotine reservoirpatches have not found their way to market yet.

A further significant problem related to patches of the reservoir typeis a higher risk of having a leakage from the patch; and in case of aleakage naturally more nicotine will be wasted in comparison to matrixand drug-in adhesive transdermal patches where the nicotine is bounde.g. in gels or other flux controlling substance.

In particular, this problem have proved significant when dealing withe.g. nicotine or nicotine derivates which are highly volatile and escapefrom the reservoir through even very small leakages even though suchleakages are under very low pressure.

It is an object of the present invention to establish a patch suitablefor release of nicotine or corresponding tobacco alkaloid, which issecure and at the same time comfortable to the user.

SUMMARY OF THE INVENTION

Reservoir patches are especially suitable for tobacco alkaloids and inparticular for nicotine due to the possibility of delivering a highconcentration of nicotine to the user.

The invention relates to a tobacco alkaloid patch (10; 41; 42; 43; 51;52; 53; 54) for transdermal administration of a tobacco alkaloid, saidpatch comprising an impermeable backing (11) and a membrane (14) whichdefines a cavity (12) there between, said membrane being permeable toand in contact with said tobacco alkaloid, said impermeable backing andsaid membrane being at least partly joined by a sealing and wherein thewidth (17) of said sealing is at least about 1 mm.

According to the invention, an improved low-area tobacco alkaloid patchhas been obtained. The patch according to the invention benefits fromhigh dose, low leakage and high user comfort.

According to an embodiment of the invention, said sealing comprises aglue sealing.

According to an embodiment of the invention, said sealing comprises aheat sealing.

According to an embodiment of the invention, the width of said sealingis at least 1.5 mm.

It is advantageous to keep the width of the sealing above a certainvalue in order to avoid leakage of reservoir content through theadhesive or through holes in the patch caused by a separation of thelayers due to a too low seal width.

According to an embodiment of the invention, the width of said sealingis at least 2.0 mm.

According to an embodiment of the invention, the width of said sealingis at most 10.0 mm.

It has been realized that an increased sealing width induces very fewbenefits, if any, as an increased sealing width causes the reservoirpatch to be less comfortable to wear for the user due to the higherstiffness all around the reservoir patch. A higher stiffness like thiswill also increase the risk of a corner or a side of the patch releasingfrom the skin of the user when placed on a curving surface as forinstance an arm or a leg.

Therefore, a sealing width will be problematic both when it is producedeither too big or too small and the present invention discloses a veryadvantageous range for the heat-sealing width.

According to an embodiment of the invention, the width of said sealingis at most 8.0 mm.

According to an embodiment of the invention, the width of said sealingis at most 6.0 mm.

According to an embodiment of the invention, said membrane and saidbacking is joined at the circumference of the patch.

According to an embodiment of the invention, said sealing comprisescircumferential sealing plus one or more sealing dots therein between.

A number of dot-formed sealings within the center of the patch willstabilize the patch and ensure a more equal distribution of gel andtobacco alkaloid.

According to an embodiment of the invention, said sealing comprises acircumferential sealing plus a pattern of any kind.

According to an embodiment of the invention, said patch comprises adetachable release liner (16).

In an embodiment of the invention, a detachable release liner isprovided in order to protect the adhesive layer and retain said tobaccoalkaloid prior to use.

According to an embodiment of the invention, said detachable releaseliner comprises one or more peelable corners.

According to an embodiment of the invention, the detachable releaseliner is attached to the membrane of the patch by an adhesive forcewhich is weaker than the adhesive force obtained by said sealing betweensaid membrane and said backing.

According to an embodiment of the invention, said tobacco alkaloidcomprises nicotine.

The term “tobacco alkaloid” as used herein and in the claims, is takento mean nicotine or nicotine-like alkaloid such as nor-nicotine,lobeline, and the like, in the free base or pharmacologically acceptableacid addition salt form. Plant alkaloids of this type are obtainablefrom species of Nicotiana, which is a source for nicotine andnor-nicotine, as well as species of Lobelia and Lobeliaceae (Indiantobacco) which are sources for lobeline.

According to an embodiment of the invention, said patch delivers morethan about 50% of the total content of tobacco alkaloid to the userwithin 24 hours from releasing the liner and placing the patch on theskin of the user.

According to an embodiment of the invention, said patch delivers morethan about 60% of the total content of tobacco alkaloid to the userwithin 24 hours from releasing the liner and placing the patch on theskin of the user.

According to an embodiment of the invention, said patch delivers morethan about 70% of the total content of tobacco alkaloid to the userwithin 24 hours from releasing the liner and placing the patch on theskin of the user.

According to an embodiment of the invention, said impermeable backingfurther comprises permeable layers, said layers may be placed on theinner side and/or on the outer side of the impermeable backing.

According to an embodiment of the invention, said impermeable backing ismade of a multilayer film.

According to an embodiment of the invention, said impermeable backing ismade of a multilayer polyester film.

According to an embodiment of the invention, said impermeable backing ismade of combinations of one or more of the following: pigmentedpolyolefin, aluminized polyester, metal foil and heat-sealablepolyolefinic layers.

According to an embodiment of the invention, said impermeable backinghas a thickness between 1 μm and 500 μm.

According to an embodiment of the invention, said impermeable backinghas a thickness between 5 μm and 200 μm.

According to an embodiment of the invention, said impermeable backinghas a thickness between 10 μm and 100 μm.

According to an embodiment of the invention, said membrane comprises apolyethylene membrane.

According to an embodiment of the invention, said membrane comprisespolyamides, such as nylon 6,6, or some grades of ethylene vinyl acetatecopolymers or functional equivalents of these.

According to an embodiment of the invention, said membrane has athickness between 1 μm and 500 μm.

According to an embodiment of the invention, said membrane has athickness between 5 μm and 200 μm.

According to an embodiment of the invention, said membrane has athickness between 10 μm and 100 μm.

According to an embodiment of the invention, said membrane isnon-porous.

According to an embodiment of the invention, said patch comprises anadhesive.

In an embodiment of the invention, said membrane of said patch is facedwith an adhesive, e.g. a tape, which may be applied to mount the patchfixedly on the skin of a user.

According to an embodiment of the invention, said patch comprises anadhesive substantially equally distributed all over the lower part ofthe patch.

According to an embodiment of the invention, said patch comprises anadhesive pattern.

An adhesive pattern may be any possible pattern. Examples of adhesivedistribution beneath the patch to be mentioned here are; acircumferential rim around the patch, a circumferential rim plus acentral point, a circumferential rim and one or more crossing lines, acircumferential rim and one or more circular rims therein between.

According to an embodiment of the invention, an adhesive layer isattached to said membrane in order to attach the patch to the skin of auser.

According to an embodiment of the invention, said cavity forms areservoir for said tobacco alkaloid.

According to an embodiment of the invention, said tobacco alkaloid iscontained within said reservoir in liquid form.

According to an embodiment of the invention, said tobacco alkaloid isconfined between said impermeable backing and said membrane within saidreservoir substantially immobilized by a viscous flowable gel.

The gel comprises e.g. purified water and a gelling agent in a suitabledistribution in order to obtain an appropriate viscosity.

According to an embodiment of the invention, said reservoir containstobacco alkaloid in an amount of less than 200 mg, preferably less than150 mg.

It is an advantage of the reservoir patch according to the inventionthat it is possible to increase the amount of tobacco alkaloid withouthaving to drastically increase the size of the patch with a followingdecreased flexibility. Hence, the reservoir patch is particularlysuitable for high-dose patches, compared to matrix patches anddrug-in-adhesive patches where a high-dose patch is equivalent to alarge-sized patch. Due to the better utilization of nicotine in thereservoir patches compared to drug-in-adhesive patches and matrixpatches, it is possible with reservoir patches to make a high-dose patchcapable of delivering twice the amount of nicotine as normal, still withless than about 50 mg of nicotine. 50 mg of nicotine is set as aninteresting upper limit as 50 mg of pure nicotine placed on the skin ofan ordinary human being is considered to be a lethal dose.

In an embodiment of the invention, an added dose may be provided whenthe user activates the patch. In this way the user receives a normal“low” dose of nicotine throughout the day and can activate the patch togive an extra dose if craving symptoms arise. The activation can beperformed by e.g. pressing the patch or in any manual or automatic way.

In an embodiment of the invention, a patch is provided comprising acombination of a matrix patch and a reservoir patch in order to utilizeadvantages from both.

According to an embodiment of the invention, said reservoir containstobacco alkaloid in an amount of less than 100 mg.

According to an embodiment of the invention, said reservoir containstobacco alkaloid in an amount of less than 50 mg.

According to an embodiment of the invention, said reservoir containstobacco alkaloid in an amount of more than 0.5 mg.

According to an embodiment of the invention, said reservoir contains agelling agent in an amount of less than 20 mg.

According to an embodiment of the invention, said reservoir contains agelling agent in an amount of less than 10 mg.

According to an embodiment of the invention, said reservoir containspurified water in an amount of less than 1000 mg.

According to an embodiment of the invention, said reservoir containspurified water in an amount of less than 800 mg.

According to an embodiment of the invention, said reservoir containstobacco alkaloid, gelling agent and purified water in a total amount ofless than 1000 mg.

According to an embodiment of the invention, said reservoir containstobacco alkaloid, gelling agent and purified water in a total amount ofless than 800 mg.

According to an embodiment of the invention, said reservoir is shaped ina rectangular, circular or oval form.

According to an embodiment of the invention, said reservoir is made upof several minor reservoirs separated by sealing.

According to an embodiment of the invention, said reservoir is shaped inthe form of a donut.

According to an embodiment of the invention, said reservoir is shaped inan essentially rectangular form with rounded corners.

According to an embodiment of the invention, said reservoir has a volumeof less than 2000 mm³. Preferably said reservoir has a volume of lessthan 1000 mm³.

According to an embodiment of the invention, said reservoir has a volumeof more than 50 mm³. Preferably said reservoir has a volume of more than100 mm³.

According to an embodiment of the invention, said patch can be separatedinto two or more separate reservoir patches.

By tearing the patch along the peel line, two or more patches that canwork individually are provided. The main patch alone or each patch maybe provided with a peel corner.

According to an embodiment of the invention, the border region(s)between said two or more reservoir patches comprises predefinedpeel-lines.

According to an embodiment of the invention, the corners of said two ormore separate reservoir patches are pre-rounded.

The patches may be pre-rounded by shaping of the reservoir patch(es)during manufacturing in such way that at least one of the patches aresubstantially free of sharp corners when peeled of and positioned on theskin of a user.

According to an embodiment of the invention, said patch can be separatedinto two or more separate patches with rounded corners.

According to an embodiment of the invention, said reservoir comprise aflux controlling gel.

According to an embodiment of the invention, said gel is constituted bypurified water and a gelling agent selected from the group ofhyroxyethyl starch, dextran, hydroxyethylcellulose (HEC),hydroxypropylmethylcellulose (HPMC), hydroxypropycellulose (HPC),methylcellulose (MC), hydroxyethyl-methylcellulose (HEMC),ethylhydroxyethylcellulose (EHEC), carboxymethyl cellulose (CMC),poly(vinyl alcohol), poly(ethylene oxide),poly(2-hydroxyethylmethacrylate), pyrolidone), and pluronics.

According to an embodiment of the invention, said gelling agent ishydroxypropyl methyl cellulose.

According to an embodiment of the invention, said gelling agent ismethyl cellulose.

According to an embodiment of the invention, said patch is colored inorder to match the skin of a user.

According to an embodiment of the invention, said patch is essentiallytransparent.

According to an embodiment of the invention, said patch is produced witha pattern or a picture on the backing.

According to an embodiment of the invention, the total size of saidpatch is less than 40 cm².

According to an embodiment of the invention, the total size of saidpatch is less than 25 cm².

According to an embodiment of the invention, said patch is rectangular,circular or oval.

Any patch shape suitable for defining a cavity between an inner and anouter surface is according to the invention.

According to an embodiment of the invention, the flexural strength ofsaid patch is below 50 mN/mm.

According to an embodiment of the invention, said reservoir furthercontains another active ingredient.

According to an embodiment of the invention, one or more enhancers areadded to enhance the uptake of said other active ingredient.

According to an embodiment of the invention, said enhancers are presentin an amount of less than 2000 mg.

Different physiologically active substances show very varying ability topenetrate the skin. Nicotine easily permeates the skin, whereas otherphysiologically active substances, typically larger in molecule size,must be assisted in order to get a noticeable amount of ingredientthrough the skin. For this purpose enhancers are used in an embodimentof the invention.

Suitable penetration enhancers (flux enhancers are preferablymonovalent, saturated or unsaturated aliphatic, cycloaliphatic oraromatic alcohols having from 4 to 12 carbon atoms, e.g. n-hexanol orcyclohexanol, aliphatic, cycloaliphatic or aromatic hydrocarbons havingfrom 5 to 12 carbon atoms, e.g. hexane, cyclohexane, isopropylbenzeneand the like, cyclo-aliphatic or aromatic aldehydes and ketones havingfrom 4 to 10 carbon atoms, such as cyclohexanone, acetamide,N,N-di-lower alkylacetamides such as N,N-dimethylacetamide orN,N-diethyl-acetamide, c.sub.10-c.sub.20-alkanoylamides, e.g.N,N-dimethyllauroylamide,1-n-C.sub.10-c.sub.20-alkylazcycloheptan-2-one, e.g.1-n-dodeclyazacycloheptan-2-one(Azone® laurocapram), orN-2-hydroxyethylacetamide, and known vehicles and/or penetrationenhancers such as aliphatic, cycloaliphatic and aromatic estersN,N-di-lower alkylsulphoxides, unsaturated oils, halogenated or nitratedaliphatic or cyclo-aliphatic hydrocarbons, salicylates, polyalkyleneglycol silicates, and mixtures thereof.

The patches according to the invention have elasticity suitable tofollow the skin of the user. As the seal width will be limiting for theelasticity of the patch, the ability to lower the seal width, asdemonstrated in the examples, increases the elasticity and hence thecomfort for the user.

In an embodiment of the invention, the Young Modulus of the patches isbelow 50 GPa irrespective of seal width.

According to an embodiment of the invention, said patch comprising animpermeable backing (17) and a membrane (14) which defines a reservoir(12) there between, said membrane (14) being permeable to and in contactwith said tobacco alkaloid, said impermeable backing (17) and saidmembrane (14) being at least partly joined by a sealing (11), whereinsaid patch has a flexural strength of less than about 250 mN/mm.

According to an advantageous embodiment of the invention, very high-dosenicotine patches may be obtained having acceptable membrane areas andfeaturing acceptable user comfort.

According to an advantageous embodiment of the invention, a high degreeof flexibility, low flexural strength, is advantageous. This is inparticular the case for people moving around a lot, e.g. craftsmen orduring sports or generally relevant to people who desire freedom to moveunrestricted.

In an embodiment of the invention, said patch has a flexural strength ofless than 150 mN/mm.

In an embodiment of the invention, said patch has a flexural strength ofless than 100 mN/mm.

In an embodiment of the invention, said patch has a flexural strength ofless than 70 mN/mm.

In an embodiment of the invention, said patch comprising an impermeablebacking (17) and a membrane (14) which defines a reservoir (12) therebetween, said membrane (14) being permeable to and in contact with saidtobacco alkaloid, said impermeable backing (17) and said membrane (14)being at least partly joined by a sealing (11), wherein said patch has aflexural strength of less than about 50 mN/mm.

According to the invention, it has been established that the flexuralstrength comparable and superior to matrix patches may be obtainedthrough a proper design by basic design parameters, and it has moreoverbeen established that bending rigidity may be relatively easily adjustede.g. by the choice of sealing pattern without compromising the choice ofmaterials.

Specifically, it has been obtained, according to the invention, thatsecure and comfortable high-dose nicotine patches may be obtained byapplying a reservoir type patch as delivery system.

Thus, it has been established that the critical backing layer may e.g.be increased in thickness or modified in structure in order tostrengthen the resulting protection from the backing if at the same timethe sealing pattern is designed to keep the overall flexural strengthlow.

A further advantage in keeping the flexural strength low is that theleakage of nicotine from the reservoir is minimized due to a reducedrisk of breaking the patch during bending and/or a reduced risk ofleakage due to partial release of the patch along the edge or cornerswhen mounted on the skin of a user.

A further and important advantage of the invention is that high dosagenicotine may be obtained even when increasing the size of the patch aslong as the flexural strength is kept below about 50 mN/mm, preferablybelow 40 mN/mm without compromising user comfort and especially thestrict non-leakage requirements related to encapsulation of nicotine orcorresponding alkaloids.

In particular, it has been established that leakage both from and intothe patch via a membrane, i.e. leakages due to insufficient mounting onthe skin of a user, has been minimized when minimizing the flexuralstrength of the complete patch.

According to a preferred embodiment of the invention, flexural strengthrefers to the ability of the patch to “bend” when mounted on the skin ofa user.

In particular, the obtained tobacco alkaloid releasing patch hasdemonstrated high-dose application and high protection against intrudingair or humidity in the interface between patch and the skin of a user.Moreover, a minimum of leakages in the backing or in the sealing hasbeen obtained due to the flexible construction.

In an embodiment of the invention, said impermeable backing (17) has aflexural strength which is greater than the flexural strength of themembrane (14).

In an embodiment of the invention, said impermeable backing has aflexural strength of at least 0.5 mN/mm.

In an embodiment of the invention, said impermeable backing has aflexural strength of at least 1 mN/mm.

According to a preferred embodiment of the invention, the flexuralstrength must be at least 1 mN/mm in order to ensure proper protectionof the membrane during use. Thus, the backing should be designed to aminimum of flexural strength in order to avoid leakage and damaging ofthe membrane.

In an embodiment of the invention, the flexural strength of theimpermeable backing is at least 0.5 mN/mm and said patch has a flexuralstrength of less than about 50 mN/mm.

In an embodiment of the invention, the flexural strength of theimpermeable backing is at least 0.5 mN/mm and said patch has a flexuralstrength of less than about 40 mN/mm.

In an embodiment of the invention, the impermeable backing of said patchhas a flexural strength of at least less than about 30 mN/mm.

In an embodiment of the invention, said patch has a flexural strength ofless than about 25 mN/mm.

In an embodiment of the invention, said patch has a flexural strength ofabout 1 to 30 mN/mm.

According to a preferred embodiment of the invention, the flexuralstrength of the nicotine releasing patch should be within a certaindesired range in order to obtain an advantageous combination of patchstrength, secure patch attachment and user comfort.

In an embodiment of the invention, the backing (17) comprises amultilayer structure.

In an embodiment of the invention, said tobacco alkaloid patch is anicotine reservoir patch.

In an embodiment of the invention, said patch has a flexural strengthgreater than about 2 mN/mm.

According to a preferred embodiment of the invention, certain rigidityis required in order to facilitate a proper distribution of (an) activesubstance(s), specifically the tobacco alkaloid. When having certainrigidity, the reservoir may maintain a constant or at least reasonablestable form.

Moreover, handling requires a minimum of rigidity when positioning thepatch on the user.

According to an advantageous embodiment of the invention it has beenshown that a sealing width too low will cause a risk of leakage ofnicotine between the backing layer and the membrane through the sealing.When the width of the sealing is lowered, the sealing will decrease inquality. On the other hand it has also been realized that the width of asealing may actually be produced lower than expected still featuring asecure sealing. This is partly believed to reside in the fact that adecreased sealing width invokes a higher flexibility in the overallpath, which in turn results in a strengthened sealing.

The drawings

The invention will now be described with reference to the drawings ofwhich

FIG. 1 illustrates a top view of an embodiment of the invention,

FIG. 2 a illustrates a side view of said embodiment of the invention,with

FIG. 2 b illustrating a magnification of FIG. 2 a in order to indicatethe different elements,

FIG. 2 c illustrating the patch of FIG. 2 b after releasing the linerand being placed on a surface,

FIGS. 3 a, 3 b, 3 c, 4 a, 4 b, 4 c, 5 a, 5 b, 5 c, 5 d, 5 e and 5 fillustrate further embodiments according to the invention, and

FIGS. 6 a and 6 b illustrate how a measurement of the flexural strengthof a patch or an element of the patch is performed.

DETAILED DESCRIPTION

A top view of a transdermal reservoir patch 10 according to anembodiment of the invention is shown in FIG. 1. The backing layer coversthe entire upper side of the patch 10, and is thus not shown; see e.g.backing layer 17 on FIG. 2 b, which prevents the reservoir content fromescaping the reservoir patch through the rear. Moreover, the backingprotects the active ingredients of the reservoir against UV radiationand moisture. Moreover, the backing serves as a shield againstmechanical impacts on the membrane. The patch 10 comprises a reservoir12 below the backing layer, a peel strip 13 and a sealing 11. The partsof the patch 10 will be explained further in the following.

The peel strip 13 facilitates removal of the liner 16 from the adhesive15 prior to mounting on the skin of a user and can be seen in FIG. 2 b.

FIG. 2 a illustrates a cross sectional view along the line I-I in FIG. 1of the above-illustrated transdermal reservoir patch 10. In order todistinguish the different layers, a magnification is shown in FIG. 2 bfrom which the layers will be explained. The transdermal reservoir patch10 comprises an impermeable backing layer 17 which provides an occlusivelayer that prevents the content of the reservoir 12 to escape into theenvironment and to protect the content of the reservoir from beingexposed to e.g. humidity or sunlight. The intended path for the contentof the reservoir 12 is through the membrane layer 14 and further throughthe adhesive layer 15 to finally reach through the skin of the user.

The different layers are sealed together giving a sealing 11 with a sealwidth w.

The impermeable backing layer 17 defines the nonskin facing, or skindistal, side of the patch in use. The material chosen should thereforebe nicotine resistant, and should exhibit minimal nicotine permeability.The backing layer should be opaque, because nicotine degrades whenexposed to ultraviolet light.

A preferred material is combinations of pigmented polyolefin, aluminizedpolyester and heat-sealable polyolefinic layers. Polyester has anicotine permeability less than 0.2 μg.100 μm/cm2.h. Preferred backingsare multilayer polyester films, available for example from 3MCorporation as Scotchpak™ 9730.

As relatively few materials are actually really sufficiently impermeableto nicotine to retain the nicotine load adequately during storage oruse, other low permeability materials that might be tried include, forexample, metal foil, metallized polyfoils, composite foils or filmscontaining polyester, Teflon (polytetrafluoroethylene) type materials,or equivalents thereof that could perform the same function.

The reservoir layer 12 may take various forms, for example, purenicotine, nicotine diluted with a liquid or immobilized by a gel. Thegel can be made from different materials preferably methyl cellulose.The reservoir layer 12 is to be a depot for the nicotine and to keep itin good contact with the membrane layer 14. The reservoir layer 12 doesnot contribute to any measurable extent to the rate-controllingmechanism.

The content of the reservoir may be any tobacco alkaloid, preferablynicotine.

The term tobacco alkaloid as used herein and in the claims, is taken tomean nicotine or nicotine-like alkaloid such as nor-nicotine, lobeline,and the like, e.g. in the free base or pharmacologically acceptable acidaddition salt form. Plant alkaloids of this type are e.g. obtainablefrom species of Nicotiana which is a source for nicotine andnor-nicotine, as well as species of Lobelia and Lobeliaceae (Indiantobacco) which are a source for lobeline.

The tobacco alkaloid may furthermore be combined with furtherphysiologically active substances which either compensates thephysically induced effect of the tobacco alkaloid of the patch or simplyadds a further functionality to the patch.

The term “physiologically active substance” as used to describe theprincipal active ingredient of the device intends a biologically activecompound or mixture of compounds that has a therapeutic, prophylactic orother beneficial pharmacological and/or physiological effect on thewearer of the device. Examples of types of drugs that may be used in theinventive device are anti-inflammatory drugs, analgesics, antiarthriticdrugs, antispasmodics, antidepressants, antipsychotic drugs,tranquilizers, antianxiety drugs, narcotic antagonists, antiparkinsonismagents, cholinergic agonists, anticancer drugs, immunosuppressionagents, antiviral agents, antibiotic agents, appetite suppressants,antiemetics, anticholinergics, antihistamines, antimigraine agents,coronary, cerebral or peripheral vasodilators, hormonal agents,contraceptive agents, antithrombotic agents, diuretics, antihypertensiveagents, cardiovascular drugs, nitroglycerine or any other nitrites andor nitrates, scopolamine or combination, oestradiol, progesterone,testosterone, diclofenac, oxibutunin, melatonin, clonodine,lidocaine/lignocaine, ibuprofen, lofexidine, nifedipine, morphine,naloxone, apomorphine, diazepam, 5-fluorouracil, buprenorphine,betahistitine, metoclopromide, taxol, cannabis, and the like. Theappropriate drugs of such types are capable of permeating through theskin either inherently or by virtue of treatment of the skin with apercutaneous absorption enhancer. Because the size of the device islimited for user-acceptance reasons, the preferred drugs are those thatare effective at low concentration in the blood stream. Examples ofspecific drugs are steroids such as estradiol, progesterone, norgestrel,levonorgestrel, norethindrone, medroxyprogesterone acetate,3-ketodesogestrel, testosterone and their esters, nitro-compounds suchas nitroglycerine and isosorbide nitrates, nicotine, chlorpheniramine,terfenadine, triprolidine, hydrocortisone, oxicam derivatives such aspiroxicam, ketoprofen, mucopolysaccharidases such as thiomucase,buprenorphine, fentanyl, naloxone, codeine, dihydroergotamine,pizotiline, salbutamol, terbutaline, prostaglandins such as misoprostoland enprostil, omeprazole, imipramine, benzamides such as metoclopamine,scopolamine, peptides such as growth releasing factor and somatostatin,clonidine, dihydropyridines such as nifedipine, verapamil, ephedrine,pindolol, metoprolol, spironolactone, nicardipine hydrochloride,calcitriol, thiazides such as hydrochlorothiazide, flunarizine,sydononimines such as molsidomine, sulfated polysaccharides such asheparin fractions and the salts of such compounds with pharmaceuticallyacceptable acids or bases. It should be noted that reservoir patchesaccording to the present invention are indeed suitable for deliveringone or more active substances chosen from the list above alone or incombination with a tobacco alkaloid.

The membrane layer 14 forms part of the rate-controlling means thatregulates the flux of nicotine from the patch to the skin. A suitablematerial is chosen by considering resistance to attack by nicotine andpossession of an appropriate permeability for nicotine. The polymerchosen for the membrane layer 14 should also be compatible with theother components, and workable by standard techniques that are used infabrication of the patch, such as casting or heat sealing. Densenon-porous membranes have a substantial advantage over micro-porousmaterials. Micro-porous membranes release the content of the patch bypore flow. Thus, in areas of the pores, the skin is exposed to rawnicotine.

Also, in the case of a volatile liquid such as nicotine, flow throughthe pores occurs rapidly so that the system is quickly exhausted and theskin is flooded with excess nicotine for the life of the patch. Incontrast, diffusion of nicotine through a non-porous film takes place bydissolution of the nicotine in the film, followed by diffusion under aconcentration gradient. By selecting materials with suitablepermeabilities, and making a membrane of appropriate thickness, it ispossible to tailor systems that can release their nicotine loadgradually over 12 or 24 hours in a safe, controlled fashion.Furthermore, the solution/diffusion mechanism protects the user's skinfrom exposure to excess amounts of raw nicotine.

Preferred membrane polymers are low-, medium-, or high-densitycommercial polyethylenes. Particularly suitable is the membraneobtainable under the trade name CoTran™ 9728 EVA from 3M but otherpolyethylene membranes faced with adhesive tapes from the 3M Corporationmight be very suitable. Other possible membrane materials arepolyamides, such as nylon 6,6, or some grades of ethylene vinyl acetatecopolymers. Functional equivalents of these are intended to be withinthe scope of the invention. The membrane layer may be formed bypreparing a solution of the chosen polymer in an organic solvent,casting on a glass plate or in a mold, and drying to evaporate thesolvent. The thickness of the finished film is tailored to give thedesired nicotine flux. A typical thickness of membranes used intransdermal patches range from about 5 μm to about 200 μm.Alternatively, it may be possible to purchase the membrane already infilm form. This type of transdermal patch may be prepared byheat-sealing the backing to the membrane layer around the perimeter ofthe patch.

The nicotine formulation may be added either before or after heatsealing. If the formulation is added before heat sealing, it isconvenient to shape the backing so as to form a cavity for retention ofthe nicotine, or to gel the nicotine. If the formulation is incorporatedafter heat sealing, the nicotine may be injected into the pouch formedby the heat-sealing process, and the injection hole sealed.

The adhesive layer 15 should be nicotine compatible and permit a usefulnicotine flux. In addition, the adhesive should satisfy the generalcriteria for adhesives used for transdermal patches in terms ofbiocompatibility, ease of application and removal, etc. Suitableadhesives for use in the practice of the invention includepressure-sensitive adhesives approved for medical use. Amine-resistanttypes are preferred, so that the adhesive will not be attacked by thenicotine. A range of useful adhesives are offered by Advanced MedicalSolutions Ltd. Particularly suitable is the AMS Pressure SensitiveAdhesive No. 10001875. Alternatively, acrylate-type adhesives with amineresistance can be used. The adhesive layer can be cast directly onto theskin-facing side of the membrane or monolith as a thin film.Alternatively, medical adhesive tape, with or without nicotine-fluxcontrolling properties, may be used.

The release liner 16 may be composed of a single layer or a multiplicityof layers. Suitable release liners may be made from materials such aspolyester, low-density polyethylene (LDPE), high-density polyethylene(HDPE), polypropylene, polystyrene, polyamide, nylon, polyvinyl chlorideand specialty papers, and include Akrosil Biorelease liners, Scotchpak1022 release liners, Adhesives Research AR5MS, Custom Coating andLaminating 7000 on HDPE or 6020 on polyethylene terephthalase (PET). Atreatment of the release liner by e.g. a layer of silicon canadvantageously be carried out to prevent an undesired sticking betweenthe adhesive layer 15 and the release liner 16. Generally, the linershould be attached to the membrane with an adhesive force which is lessthan the adhesive force keeping the membrane to the backing in order toavoid damaging the sealing or the membrane when releasing the liner.

The sealing 11 can be performed by gluing the layers together orpreferably by heat sealing the layers. In any case the sealing will havea certain sealing width was indicated in FIG. 2 b. Said sealing width wwill have a crucial influence on the functionality of the reservoirpatch. In case of a too small sealing width there will be a risk ofleakage of the reservoir content sideways through the sealing and intothe surroundings. On the other hand, a too big sealing width will causethe reservoir patch to be less comfortable to wear for the user due tothe higher stiffness all around the reservoir patch. A higher stiffnesslike this will also increase the risk of release of a corner or a sideof the patch from the skin of the user when placed on a curved surfaceas for instance an arm or a leg. If a corner or a side of the reservoirpatch is released from the skin there will immediately be a risk of thereservoir content to escape to the surroundings. This risk will behigher over time as a released part of a patch will have a tendency tospread and cause an even bigger part of the patch to be released.

FIG. 2 c illustrates the patch 10 after release of the liner 16 andplacement on a surface 20. This surface may be any surface but is mostlikely to be the skin of a user of the reservoir patch. The patch is tobe placed on the skin, preferably on a skin spot with a small amount ofhair and preferably on a place with thin skin. The patch 10 is attachedto the skin with the help of the adhesive layer 15.

FIGS. 3 a, 3 b, 3 c, 4 a, 4 b, 5 a, 5 b, 5 c, 5 d and 5 e illustratefurther embodiments according to the present invention. FIGS. 3 a, 3 band 3 c illustrate different sizes 31, 32 and 33 of the reservoir patchas a whole. FIG. 4 a illustrates an embodiment of the invention 41. Theillustrated patch 41 comprises a sealing 11 which serves to establish areservoir between a backing and a membrane (not shown). The illustratedpatch comprises a peel corner 13. The further patch components may e.g.correspond to the patch components already described in FIGS. 1 to 2 c.For reasons of explanation, the patch 41 is referred to as a startingpoint when explaining further embodiments. It should be noted thatnumerous variations in size, shape and so on may be applied within thescope of the invention.

FIG. 4 b illustrates a patch 42 provided with an extra peel corner 13 a.The further patch components may e.g. correspond to the patch componentsalready described in FIGS. 1 to 2 c. This variant facilitates easierrelease of the liner. Further numbers of peel corners, sizes of peelcorners or peel areas may be applied within the scope of the invention.Generally, according to the invention, peel corners are preferred butoptional. FIG. 4 c illustrates a further embodiment of the invention 43where a seal width w of the sealing 11 is decreased in order to increasethe flexibility and/or decrease the flexural strength of the patch 43structure.

FIGS. 5 a-5 f illustrate further embodiments according to the inventionconcerning variations in the seal structure. FIG. 5 a shows a patch 51with a sealing 11 and a peel corner 13. The further patch components ofthe patches in FIGS. 5 a to 5 f may e.g. correspond to the patchcomponents already described in FIGS. 1 to 2 c. The patch 51 is providedwith an extra seal spot 520 within the middle of the reservoir in orderto stabilize the backing and the reservoir. Stabilization here will keepthe shape of the reservoir and maintain the distribution of gel. Afurther variant is illustrated for the patch 52 in FIG. 5 b where twoseal spots 521 and 522 are provided. Any number of spots can in this waybe provided in order to stabilize the patch according to the presentinvention.

FIG. 5 c shows a patch 53 provided with an extra sealing between themembrane and the backing crossing the patch, thereby splitting the patchinto two separate patches with separate reservoirs 12 a and 12 b. Theextra sealing is split by a peel line 523 with which the two patches caneasily by separated. In this way the patch can be used as normal if justplaced on the skin as whole. In addition to that it is possible to splitthe patch into two separate patches, each of which giving e.g. half thedose, by tearing along the peel line 523. A further embodiment is shownin FIG. 5 d illustrating a patch 54 provided with two extra sealingsseparating the patch into four separate patches each with e.g. onefourth of the total dose. Generally for the patches illustrated in FIGS.5 a to 5 e, it should be noted that numerous variations in size, shapeand so on may be applied within the scope of the invention.

FIG. 5 e shows a further embodiment of the embodiments shown in FIGS. 5c and 5 d. A patch 55 where all corners, subject to be exposed whenseparating the patches, are rounded beforehand in order for the user toavoid sharp corners when separating the patches through the peel line524. This rounding may preferably be established during manufacturing ofthe patch.

FIG. 5 f shows a cross-sectional view along the line II-II of the patch55 in FIG. 5 e and might as well have been of any the patches in FIGS. 5c and 5 d. The widths of the reservoir defining seals are marked w.

Different physiologically active substances show very varying ability topenetrate the skin. Nicotine easily permeates the skin, whereas otherphysiologically active substances, typically larger in molecule size,must be assisted in order to get a noticeable amount of ingredientthrough the skin. For this purpose enhancers are used in an embodimentof the invention.

Suitable penetration enhancers, flux enhancers, are preferablymonovalent, saturated or unsaturated aliphatic, cycloaliphatic oraromatic alcohols having from 4 to 12 carbon atoms. e.g. n-hexanol orcyclohexanol, aliphatic, cycloaliphatic or aromatic hydrocarbons havingfrom 5 to 12 carbon atoms, e.g. hexane, cyclohexane, isopropylbenzeneand the like, cyclo-aliphatic or aromatic aldehydes and ketones havingfrom 4 to 10 carbon atoms, such as cyclohexanone, acetamide,N,N-di-lower alkylacetamides such as N,N-dimethylacetamide orN,N-diethyl-acetamide, c.sub.10-c.sub.20-alkanoylamides, e.g.N,N-dimethyllauroylamide,1-n-C.sub.10-c.sub.20-alkylazcycloheptan-2-one, e.g.1-n-dodeclyazacycloheptan-2-one(Azone® laurocapram), orN-2-hydroxyethylacetamide, and known vehicles and/or penetrationenhancers such as aliphatic, cycloaliphatic and aromatic esters N,N-di-lower alkylsulphoxides, unsaturated oils, halogenated or nitratedaliphatic or cyclo-aliphatic hydrocarbons, salicylates, polyalkyleneglycol silicates, and mixtures thereof.

The following examples will further illustrate embodiments of thepresent invention. It is to be understood that the examples set forthare illustrative and not limiting for the present invention.

All patches used in the following examples were made without tobaccoalkaloid, hence the possibility for and amount of loss of tobaccoalkaloid due to e.g. evaporation is expected to be significantly less inthe tests compared to a final product according to the presentinvention.

Example 1

Six volunteers each wore patches according to the general provisions ofthe invention with heat-seal widths of: 0.5, 1, 1.5, 2, 3, 4, and 5 mm.After approximately 16 hours of wear, observations were collectedregarding irritation, malfunctioning, loss of content and so on.

As a whole a tendency was seen towards higher risk of leakage withdecreasing seal widths. This ultimately led to three volunteers of thetotal of six volunteers experiencing a leakage of reservoir content forthe patches with a seal width of 0.5 mm.

Example 2

A standard leakage test was carried out on the patches according to thegeneral provisions of the invention for the series of heat-seal widths1, 2, 3, 4, and 5 mm for the sizes of 8 cm² and 17 cm² of new patchesand for the 17 cm² worn for a day in example 1.

The patch to be measured on is placed between two plane metal plates,the upper plate is moving downwards with a speed of 1 mm/min which givesan increasing force equally distributed over the patch area, causing itto be pressed towards the lower plate. At a certain stage the patch willstart to leak, at which stage the so-called burst force is measured.

The observed values can be seen in table 1.

TABLE 1 Patch area = 8 cm2 Burst Patch area = 17 cm2 Burst Seal Width(mm) Force (N) Seal Width (mm) Force (N) 5 2052 5 686 4 1281 4 425 31404 3 778 2 919 2 198 1 52 1 35

We observe a tendency of higher risk of leakage for the smallerheat-sealing widths. On the other hand it is noted that an acceptablesealing width is actually much lower than expected.

From examples 1 and 2 we estimate a useable heat-seal width of above atleast 1 mm and an optimal heat-seal width above at least 2 mm.

Example 3

It has been an object according to an embodiment of the invention toobtain a low flexural strength nicotine patch. The patch shouldpreferably be a high-dose patch. The object of the test was to determineapplicable measures by which the desired flexural strength may beobtained. The flexural strength intended to be obtained was not morethan about 50 mN/mm.

As already described, the applied patch should have a low flexuralstrength in order to obtain a safe attachment to the skin of a user andin order to minimize the annoyance of the user when applying the patch.

A test was carried out, whether the desired flexural strength test maybe obtained at all. The test was carried out on two different sizes ofthe patch according to the general provisions of the invention, and on aprior art matrix patch and a prior art drug-in-adhesive patch both ofthe latter are products currently on the market. The test was founded onthe basis of the ISO 178 standard. The release liner was detached andthe patch was placed on a support span of 30 mm so that it may besubject to a horizontally strained influence through the three-pointbending. The results of the measurements are shown below in table 2.Flexural strength is measured in mN/mm.

TABLE 2 Flexural Strength (mN/mm) 1. measure 2. measure AverageFull-size I1 19.6 28.1 24 I2 failed 10.2 10 PA1 67.2 54.8 61 PA2 71.461.0 66 Cut into 20 × 37 mm² I3 24.1 20.3 22 I4 2.2 2.7 2 PA3 21.1 21.121 PA4 26.4 23.0 25

I1 and I2 are both reservoir patches sized 17 cm² according to twoembodiments of the invention. The main difference between I1 and I2 isthe seal width which for I1 is 5 mm and for 12 is 2.5 mm. PA1 is a priorart drug-in-adhesive patch and PA2 is a prior art matrix patch. Both PA1and PA2 are products commercially available. I3 and I4 are bothreservoir patches according to two further embodiments of the invention.I3 has a size of 20×37 mm² with a seal width of 5 mm included and I4 issimilar to I1 but cut into the size of 20×37 mm² without a seal width.PA3 is similar to PA1 but cut into the size of 20×37 mm², and PA4 issimilar to PA2 but cut into the size of 20×37 mm².

A clear tendency is seen when focusing on the three measurementsperformed on the 17 cm² patches, I1, I2 and I4 according to theinvention. The flexural strength is seen to be 24 mN/mm for the patch I1with 5 mm seal, 10 mN/mm for the patch with 2.5 mm seal I2 and only 2mN/mm for the patch I4 where the two side seals have been cut off whenproviding the cut 20×37 mm2 on the basis of the I1 patch.

Accordingly, for the reservoir patch according to the invention, it isnoted that the seal may be adjusted suitably in order to obtain thedesired flexural strength when having a certain requirement to nicotinecontent. This fact is underlined by the fact that the flexural strengthdecreases significantly, when decreasing the seal width. On the otherand, it is also noted that an increasing of the membrane area of thepatch, from about 8 cm2 of I3 to about 17 cm2 of I1 results in a verymoderate increasing of flexural strength. This underlines the fact thata high-dose release may be obtained in a secure and comfortable way bymeans of a reservoir patch having a flexural strength of less than about50 mN/mm, whereas the drug-in-adhesive and matrix patches PA1 to PA4both lack the required low flexural strength and moreover feature arelatively low dose.

Moreover, as already established from the burst force test, a seal widtheven below 2 mm still provides a patch capable of keeping the contentinside the reservoir and protecting the content of the reservoir againstthe environment.

When considering the drug-in-adhesive patches and matrix patches, weobserve for both of them that the flexural strength for the cut outpiece constitutes approximately one third of the flexural strength ofthe corresponding full-size patch. On the contrary for the reservoirpatches going from the 8 cm² to the 17 cm² patch an increase only from22 to 24 mN/mm is seen. Hence, reservoir patches according to thepresent invention do not suffer from problems with unpleasantflexibility when increasing the membrane area, as the sealing does notneed to be broader in order to keep the reservoir content inside.

A comparison between the full-size patches of drug-in-adhesive, matrixand reservoir according to the invention indicates that the reservoirpatches have a flexural strength (24 and 22 mN/mm) that indicates higherflexibility and comfort for the user compared with drug-in-adhesive (61mN/mm) and matrix (66 mN/mm).

Example 4

A bar test was carried out on two different sizes of the patch accordingto the general provisions of the invention and on a matrix patch and adrug-in-adhesive patch—both of the latter are products currently on themarket.

PU-foil is used as bar, as it is experienced by the inventor thatPU-foil resembles skin the most. In order to have conditions resemblingthe realistic situation the temperature of the setting is 35° C. similarto a typical skin temperature.

All four patches were glued to bars with four different diameters, 50,40, 30 and 20 mm and then left there for 24 hours to see whether thelong time in skin-similar conditions would affect the ability to stickto the bar.

It turned out that both of the patches according to the generalprovisions of the invention and the matrix patch stood the conditionsand stuck to the bar for all 24 hours, whereas the drug-in-adhesivepatch began to loose grip for diameters of 40, 30 and 20 mm.

Hence, nicotine patches according to the general provisions of theinvention turn out to be advantageous in comparison to drug-in-adhesivepatches.

Example 5

The tests for flexural strength referred to in the description are basedon the ISO 178 standard unless otherwise stated. The test measures theforce required to bend a material under 3 point loading conditions asillustrated in FIGS. 6 a and 6 b. A material 62 for which the flexuralstrength is to be measured is placed on a support span provided bysupport structures 60 and 61. In the middle of the material 62 a roll 63presses down on the material and the necessary force to move thematerial d mm down is measured within a certain range.

The separation between the support structures 60 and 61 was 30 mm. Thevelocity of the roll 63 to bend the material 62 was 5 mm/min. The valueswere found by measuring the necessary force to move the materialdownwards from d=1 mm to d=5 mm. References to flexural strength relatesto patches according to the invention are referred to theabove-mentioned measuring method unless otherwise stated.

1. A tobacco alkaloid patch for transdermal administration of a tobaccoalkaloid, said patch comprising an impermeable backing having an innerside and an outer side and a membrane which defines a cavity having acircumference there between, said membrane being permeable to and incontact with said tobacco alkaloid, said impermeable backing and saidmembrane being at least partly joined by a sealing having a width andwherein the width of said sealing is at least about 1 mm and wherein anadhesive force for said sealing is present between said membrane andsaid backing.
 2. The tobacco alkaloid patch according to claim 1,wherein said sealing comprises a glue sealing.
 3. The tobacco alkaloidpatch according to claim 1, wherein said sealing comprises a heatsealing.
 4. The tobacco alkaloid patch according to claim 1, wherein thewidth of said sealing is at least 1.5 mm.
 5. The tobacco alkaloid patchaccording to claim 1, wherein the width of said sealing is at least 2.0mm.
 6. The tobacco alkaloid patch according to claim 1, wherein thewidth of said sealing is at most 10.0 mm.
 7. The tobacco alkaloid patchaccording to claim 1, wherein the width of said sealing is at most 8.0mm.
 8. The tobacco alkaloid patch according to claim 1, wherein thewidth of said sealing is at most 6.0 mm.
 9. The tobacco alkaloid patchaccording claim 1, wherein said membrane and said backing are joined atthe circumference of the patch.
 10. The tobacco alkaloid patch accordingto claim 1, wherein said sealing comprises a circumferential sealing andone or more sealing dots therein between.
 11. The tobacco alkaloid patchaccording to claim 1, wherein said sealing comprises a circumferentialsealing and a pattern.
 12. The tobacco alkaloid patch according to claim1, wherein said patch comprises a detachable release liner.
 13. Thetobacco alkaloid patch according to claim 12, wherein said detachablerelease liner comprises one or more peelable corners.
 14. The tobaccoalkaloid patch according to any of the claim 12, wherein the detachablerelease liner is attached to the membrane of the patch by an adhesiveforce which is weaker than the adhesive force obtained by said sealingbetween said membrane and said backing.
 15. The tobacco alkaloid patchaccording to claim 1, wherein said tobacco alkaloid comprises nicotine.16. The tobacco alkaloid patch according to claim 12, wherein said patchdelivers more than about 50% of the tobacco alkaloid to a user within 24hours from releasing the liner and placing the patch on of the user'sskin.
 17. The tobacco alkaloid patch according to claim 12, wherein saidpatch delivers more than about 60% of the tobacco alkaloid to a userwithin 24 hours from releasing the liner and placing the patch on of theuser's skin.
 18. The tobacco alkaloid patch according to claim 12,wherein said patch delivers more than about 70% of the tobacco alkaloidto a user within 24 hours from releasing the liner and placing the patchon the skin of the user's skin.
 19. The tobacco alkaloid patch accordingto any of the claim 1, wherein said impermeable backing furthercomprises permeable layers, wherein said permeable layers may be placedon the inner side and/or on the outer side of the impermeable backing.20. The tobacco alkaloid patch according to any of the claim 1, whereinsaid impermeable backing is made of a multilayer film.
 21. The tobaccoalkaloid patch according to claim 1, wherein said impermeable backing ismade of a multilayer polyester film.
 22. The tobacco alkaloid patchaccording to claim 1, wherein said impermeable backing is selected frompigmented polyolefin, aluminized polyester, metal foil, heat-sealablepolyolefinic layers, and combinations thereof.
 23. The tobacco alkaloidpatch according to claim 1, wherein said impermeable backing has athickness between 1 μm and 500 μm.
 24. The tobacco alkaloid patchaccording to claim 1, wherein said impermeable backing has a thicknessbetween 5 μm and 200 μm.
 25. The tobacco alkaloid patch according toclaim 1, wherein said impermeable backing has a thickness between 10 μmand 100 μm.
 26. The tobacco alkaloid patch according to claim 1, whereinsaid membrane comprises a polyethylene membrane.
 27. The tobaccoalkaloid patch according to claim 1, wherein said membrane comprisespolyamides.
 28. The tobacco alkaloid patch according to claim 1, whereinsaid membrane has a thickness between 1 μm and 500 μm.
 29. The tobaccoalkaloid patch according to claim 1, wherein said membrane has athickness between 5 μm and 200 μm.
 30. The tobacco alkaloid patchaccording to claim 1, wherein said membrane has a thickness between 10μm and 100 μm.
 31. The tobacco alkaloid patch according to claim 1,wherein said membrane is non-porous.
 32. The tobacco alkaloid patchaccording to claim 1, wherein said patch comprises an adhesive.
 33. Thetobacco alkaloid patch according to claim 32, wherein said adhesive issubstantially equally distributed over a lower portion of the patch. 34.The tobacco alkaloid patch according to any of the claim 1, wherein saidpatch comprises an adhesive pattern.
 35. The tobacco alkaloid patchaccording to claim 1, wherein an adhesive layer is attached to saidmembrane.
 36. The tobacco alkaloid patch according to any of the claim1, wherein said cavity forms a reservoir for said tobacco alkaloid. 37.The tobacco alkaloid patch according to claim 36, wherein said tobaccoalkaloid is contained within said reservoir in liquid form.
 38. Thetobacco alkaloid patch according to claim 37, wherein said tobaccoalkaloid is confined between said impermeable backing and said membranewithin said reservoir and is substantially immobilized by a viscousflowable gel.
 39. The tobacco alkaloid patch according to claim 36,wherein said reservoir contains the tobacco alkaloid in an amount ofless than 200 mg.
 40. The tobacco alkaloid patch according to claim 36,wherein said reservoir contains the tobacco alkaloid in an amount ofless than 100 mg.
 41. The tobacco alkaloid patch according to claim 36,wherein said reservoir contains the tobacco alkaloid in an amount ofless than 50 mg.
 42. The tobacco alkaloid patch according to claim 36,wherein said reservoir contains the tobacco alkaloid in an amount ofmore than 0.5 mg.
 43. The tobacco alkaloid patch according to claim 36,wherein said reservoir contains a gelling agent in an amount of lessthan 20 mg.
 44. The tobacco alkaloid patch according to claim 36,wherein said reservoir contains a gelling agent in an amount of lessthan 10 mg.
 45. The tobacco alkaloid patch according to claim 36,wherein said reservoir contains purified water in an amount of less than1000 mg.
 46. The tobacco alkaloid patch according to claim 36, whereinsaid reservoir contains purified water in an amount of less than 800 mg.47. The tobacco alkaloid patch according to claim 36, wherein saidreservoir contains the tobacco alkaloid, a gelling agent and purifiedwater in a total amount of less than 1000 mg.
 48. The tobacco alkaloidpatch according to claim 36, wherein said reservoir contains the tobaccoalkaloid, a gelling agent and purified water in a total amount of lessthan 800 mg.
 49. The tobacco alkaloid patch according to claim 36,wherein said reservoir is shaped in a rectangular, circular or ovalform.
 50. The tobacco alkaloid patch according to claim 36, wherein saidreservoir is made up of several minor reservoirs separated by sealing.51. The tobacco alkaloid patch according to claim 36, wherein saidreservoir is shaped in the form of a donut.
 52. The tobacco alkaloidpatch according to claim 36, wherein said reservoir is shaped in arectangular form with rounded corners.
 53. The tobacco alkaloid patchaccording to claim 36, wherein said reservoir has a volume of less than2000 mm³.
 54. The tobacco alkaloid patch according to claim 36, whereinsaid reservoir has a volume of more than 50 mm³.
 55. The tobaccoalkaloid patch according to claim 36, wherein said patch can beseparated into two or more separate reservoir patches having borderregions with corners between said two or more reservoir patches.
 56. Thetobacco alkaloid patch according to claim 55, wherein the border regionsbetween said two or more reservoir patches comprise predefinedpeel-lines.
 57. The tobacco alkaloid patch according to claim 55,wherein the corners of said two or more separate reservoir patches arepre-rounded.
 58. The tobacco alkaloid patch according to claim 1,wherein said patch can be separated into two or more separate patcheswith rounded corners.
 59. The tobacco alkaloid patch according to claim36, wherein said reservoir comprises a flux-controlling gel.
 60. Thetobacco alkaloid patch according to claim 59, wherein saidflux-controlling gel comprises purified water and a gelling agentselected from the group of hydroxyethyl starch, dextran,hydroxyethylcellulose (HEC), hydroxypropylmethylcellulose (HPMC),hydroxypropycellulose (HPC), methylcellulose (MC),hydroxyethyl-methylcellulose (HEMC), ethylhydroxyethylcellulose (EHEC),carboxymethyl cellulose (CMC), poly(vinyl alcohol), poly(ethyleneoxide), poly(2-hydroxyethylmethacrylate), pyrolidone), and pluronics.61. The tobacco alkaloid patch according to claim 60, wherein saidgelling agent is hydroxypropyl methyl cellulose.
 62. The tobaccoalkaloid patch according to claim 60, wherein said gelling agent ismethyl cellulose.
 63. The tobacco alkaloid patch according to claim 1,wherein said patch is colored in order to match the skin of a user. 64.The tobacco alkaloid patch according to claim 1, wherein said patch isessentially transparent.
 65. The tobacco alkaloid patch according toclaim 1, wherein said patch is produced with a pattern or a picture onthe backing.
 66. The tobacco alkaloid patch according to claim 1,wherein the patch is less than 40 cm².
 67. The tobacco alkaloid patchaccording to claim 1, wherein the patch is less than 25 cm².
 68. Thetobacco alkaloid patch according to claim 1, wherein said patch isrectangular, circular or oval.
 69. The tobacco alkaloid patch accordingto claim 1, wherein said patch has a flexural strength below 50 mN/mm.70. The tobacco alkaloid patch according to claim 36, wherein saidreservoir further contains at least one additional active ingredient.71. The tobacco alkaloid patch according to any of the claim 70, whereinone or more enhancers are added to the reservoir to enhance the uptakeof the additional active ingredient.
 72. The tobacco alkaloid patchaccording to claim 71, wherein said enhancers are present in an amountof less than 2000 mg.
 73. The tobacco alkaloid patch according to claim1, wherein said patch has a flexural strength of less than about 250mN/mm.
 74. The tobacco alkaloid patch according to claim 1, wherein saidpatch has a flexural strength of less than about 50 mN/mm.
 75. Thetobacco alkaloid patch according to claim 1, wherein said impermeablebacking has a flexural strength which is greater than the flexuralstrength of the membrane.
 76. The tobacco alkaloid patch according toclaim 1, wherein said impermeable backing has a flexural strength of atleast 0.5 mN/mm.
 77. The tobacco alkaloid patch according to claim 1,wherein said impermeable backing has a flexural strength of at least 1mN/mm.
 78. The tobacco alkaloid patch according to claim 1, wherein theimpermeable backing is has a flexural strength of at least 0.5 mN/mm andwherein said patch has a flexural strength of less than about 50 mN/mm.79. The tobacco alkaloid patch according to claim 1, wherein theimpermeable backing has a flexural strength of at least 0.5 mN/mm andwherein said patch has a flexural strength of less than about 40 mN/mm.80. The tobacco alkaloid patch according to claim 1, wherein theimpermeable backing of said patch has a flexural strength of less thanabout 30 mN/mm.
 81. The tobacco alkaloid patch according to claim 1,wherein said patch has a flexural strength of less than about 25 mN/mm.82. The tobacco alkaloid patch according to claim 1, wherein said patchhas a flexural strength of about 1 to 30 mN/mm.
 83. The tobacco alkaloidpatch according to claim 1, wherein the impermeable backing comprises amultilayer structure.
 84. The tobacco alkaloid patch according to claim1, wherein said tobacco alkaloid patch is a nicotine reservoir patch.85. The tobacco alkaloid patch according to claim 1, wherein said patchhas a flexural strength greater than about 2 mN/mm.